Switching from aerobic glycolysis to oxidative phosphorylation modulates the sensitivity of mantle cell lymphoma cells to TRAIL

Abstract

TRAIL (TNF (tumour necrosis factor)-related apoptosis-inducing ligand) a putative anti-cancer cytokine induces apoptosis through DISC (death-inducing signalling complex)-mediated activation of caspase-8 and/or cleavage of Bid. TRAIL is relatively specific for tumour cells but primary chronic lymphocytic leukaemia and mantle cell lymphoma (MCL) cells are resistant. Herein, we show that cellular metabolism influences cell death and that MCL cells (Z138 cell line) can survive/proliferate in glucose-free media by switching from aerobic glycolysis to 'coupled' oxidative phosphorylation. Extracellular flux analysis and mitochondrial inhibitors reveal that in the absence of glycolysis, Z138 cells have enhanced respiratory capacity coupled to ATP synthesis, similar to 'classical' state 3 mitochondria. Conversely, 2-deoxyglucose (2DG) blocked glycolysis and partially inhibited glycolyticdependent oxidative phosphorylation, resulting in a 50% reduction in cellular ATP levels. Also, 2DG sensitised Z138 cells to TRAIL and induced a marked decrease in caspase-8, -3, cFLIP S , Bid and Mcl-1 expression but Bak remained unchanged, altering the Mcl-1/Bak ratio, facilitating cytochrome c release and cell death. Conversely, under glucose-free conditions, Z138 cells were less sensitive to TRAIL with reduced TRAIL-R1/R2 surface receptor expression and impaired DISC formation. Anti-apoptotic proteins Bcl-2 and XIAP were up-regulated while pro-apoptotic BAX was down-regulated. Additionally, mitochondria had higher levels of cytochrome c and ultrastucturally exhibited a condensed configuration with enhanced intracristal spaces. Thus, metabolic switching was accompanied by mitochondrial proteome and ultrastructural remodelling enabling enhanced respiration activity. Cytochrome c release was decreased in glucose-free cells, suggesting that either pore formation was inhibited or that cytochrome c was more tightly bound. Glucose-free Z138 cells were also resistant to intrinsic cell death stimuli (ABT-737 and ionising radiation). In summary, in MCL cells, the anti-glycolytic effects of 2DG and glucose restriction produced opposite effects on TRAIL-induced cell death, demonstrating that mitochondrial metabolism directly modulates sensitivity of tumour cells to apoptosis.

Challenges in targeting cancer metabolism for cancer therapy

“…However, it seems unlikely that the diversity of the metabolomes, extending over 43 essential genes in three prostate cancer cell lines, can be explained by the status of PTEN Given this metabolic flexibility, even if an efficacious target for a cancer patient can be found, might the cancer just elude a metabolic inhibitor-based therapy by altering its own metabolism? This has been shown in an established cell line by Robinson and colleagues [9]. Z138 mantel lymphoma cells incubated in glucose-depleted media supplemented with pyruvate and glutamine easily survived the adverse conditions by switching to aerobic respiration.…”

2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy

“…After entering the cell, 2DG is phosphorylated by HK to form 2-Deoxy-D-glucose-6-phosphate (2DG-6-P), which cannot be further metabolized via glycolysis but accumulates and noncompetitively inhibits HK and competitively inhibits PGI [7,38,43]. Because 2DG inhibits the first critical steps at the beginning of glucose metabolism, both glycolysis and OXPHOS may be partially disrupted [44]. These events lead to decreased ATP production, blocked cell cycle, decreased and inhibited cell growth and even cell death [6,16,40].…”

Metabolic responses of HeLa cells to silica nanoparticles by NMR-based metabolomic analyses

“…In our study, a higher lactate/alanine ratio was observed in the high-dosage group (30.3 ± 5.8 vs 13.4 ± 8.8 of control, p \ 0.01) at 6 h post-treatment of silica nanoparticles, which indicated a higher reductive/lower oxidative state of the HeLa cells. The reduced ATP in our study may be related to oxidative phosphorylation in mitochondria (Robinson et al 2012 which was promoted by the activation of transcription factor-2 (ATF-2) (Mohamed et al 2011), a member of the basic transcription factor family that regulates the expression of genes in response to various stress signals (Gupta et al 1995). However, such conclusion needs to be further tested in the possible animal experiment.…”